Our major accomplishments are in the following areas:[unreadable] [unreadable] 1) Bmp4 is required for the formation of the apparatus that detects angular head movements (manuscript published)[unreadable] Our ability to detect angular head movements is dependent on the vestibular portion of the inner ear consisting of three semicircular canals and their associated sensory structures, the cristae. The genetic control for the formation of this apparatus is largely unknown. In this study, using conditional knockout approaches in mice and transient gene expression in chicken, we demonstrate that BMP4, a member of the Transforming Growth Factor - &#946; family, is responsible for the formation of the entire apparatus that detects angular head movements. We show that Bmp4 expressed in the prospective crista is required for its formation as well as the formation of its associated non-sensory structure, the semicircular canals. Bmp4 does not mediate crista formation by regulating the known prosensory genes required for the formation of sensory hair cells and supporting cells in the inner ear. Instead, genes that are readily affected by the down-regulation of BMP signaling appear to be the ones eventually expressed in the non-sensory region of a mature crista. Thus, these results suggest that BMP4 has a global role in organizing the structural formation of the crista into sensory and non-sensory domains, as well as instructing canal formation.[unreadable] [unreadable] 2) Noggin heterozygous mice an animal model for conductive hearing loss in human (manuscript published)[unreadable] Animal models are often used to study human genetic disorders. This project explores the genetic etiology of conductive hearing loss in humans using Noggin heterozygous mice. We show that Noggin heterozygous mice suffer from conductive hearing loss, similar to patients with NOGGIN mutations. The cause of hearing loss in the mutant mice is due to an ectopic bone fragment connecting one of the middle ear ossicles, the stapes, to the wall of the middle ear, which impedes ossicle vibrations during sound conduction. The genetic cause of this ectopic bone fragment is due to incomplete separation between the stapes and its primordial cartilage element due to unopposed Bone morphogenetic protein activities during development. Our study infers that haploinsufficiency is the cause of human patients associated with autosomal dominant disorders of NOGGIN mutations, and reducing the levels of Bone Morphogenetic proteins is a relevant mode of treatment to be explored clinically. [unreadable] [unreadable] 3) Functions of Lmx1a in inner ear formation (manuscript in preparation)[unreadable] Lmx1a is a Lim-domain transcription factor that is required for neural tube and inner ear development. We investigated the role of Lmx1a in inner ear formation by analyzing the inner ear phenotypes of a spontaneous mouse mutant, dreher, in which the Lmx1a allele contains a point mutation in one of its Lim-homeodomains. The inner ears of dreher mutants are poorly developed morphologically, lacking the endolymphatic duct and semicircular canals. The cochlear duct is also shortened. While individual sensory patches are present within the amorphic membranous chamber, the size and shape of each sensory structure is often malformed. Our gene expression analyses indicate that Lmx1a is required for maintaining proper boundaries among different inner ear domains. [unreadable] [unreadable] [unreadable] 4) Gradient of retinoic acid signaling dictates the antero-posterior axis of the inner ear (manuscript in preparation)[unreadable] Proper formation of the intricate, three-dimensional inner ear structure relies on signaling molecules from its surrounding tissues for positional cues. While signaling molecules from the hindbrain are important for establishing the dorsal-ventral (D/V) axis of the inner ear, the specification of the anterior-posterior (AP) axis is thought to be independent of the hindbrain. Using tissue transplantation and bead implantation techniques in ovo, we show that the genetic control of the AP orientation of the inner ear structure relies on graded retinoic acid signaling along the ear primordium during early stages of embryogenesis. This gradient is presumably generated by retinoic acid degradation enzymes expressed in the ectoderm and mesoderm rostral to the inner ear and retinoic acid produced caudally by the somites.